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At least 1,621 records · Page 90Linked to original sources
PubMed1988

Analysis of mechanisms of free-energy coupling and uncoupling by inhibitor titrations: theory, computer modeling and experiments.

The rates of ATP synthesis and of ATP-driven NAD reduction have been measured in bovine heart submitochondrial particles as a function of the fraction of inhibited redox pumps (in titrations with either antimycin or rotenone) and of the fraction of inhibited ATPases (in titrations with DCCD). The flux control coefficients of the redox and ATPase proton pumps on the rates of ATP synthesis and of ATP-driven NAD reduction have been derived and found to be equal to 1 for both pumps; i.e., both pumps appear to be 'completely rate limiting'. A theoretical analysis of the inhibitor titration approach based on kinetic models of chemiosmotic coupling and on the theory of metabolic control is presented. This analysis (i) shows that the results of the single inhibitor titrations are incompatible with a delocalized chemiosmotic mechanism of energy coupling if the proton conductance of the membrane is sufficiently low with respect to the conductances of the pumps; and (ii) suggests an experimental approach based on the determination of the P/O and the respiratory control ratios at different degrees of inhibition of the proton pumps to establish the origin of the 'loose coupling' of submitochondrial particle preparations. Three independent types of observation show that the 'loose coupling' of the particle preparation is not mainly due to an increased membrane proton conductance. The same and other independent observations are consistent with the view that the loose coupling of submitochondrial particle preparation is due mainly to inhomogeneity, i.e. to the presence of a subpopulation of highly leaky non-phosphorylating vesicles respiring at maximal rate. The results as a whole together with the simulations and analysis presented lead to the conclusion that the mechanism of free-energy coupling in submitochondrial particles is not completely delocalized.

Adenosine Triphosphatases↗
PubMed2006

Discovery of novel isothiazole inhibitors of the TrkA kinase: structure-activity relationship, computer modeling, optimization, and identification of highly potent antagonists.

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.

Cell Line, Tumor↗
PubMed2001

Ventilation and radon transport in Dutch dwellings: computer modelling and field measurements.

In 1995 and 1996 radon concentrations and effective air flows were measured in approximately 1500 Dutch dwellings built between 1985 and 1993. The goal of this investigation was to describe the trend in the average radon concentration by supplementing the first survey on dwellings built up to 1984 and to quantify the contributions of the most important sources of radon. In the living room of new dwellings the average radon concentration was 28 Bq m(-3), which is 50% higher than in dwellings built before 1970. Measurements of effective air flows showed the most important source of radon in the living room of new dwellings to be the building materials, with an average contribution of 70%. The other 30% comprised outside air and air from the crawl space in equal quantities. The long-term increase in the indoor radon concentration is mainly due to improvements in insulation since 1970, resulting in a fourfold decrease in infiltration through the building shell. Model calculations, supplementing the field measurements, confirmed the dominant effect of increasing airtightness of dwellings compared to effects of the observed trend in the use of building materials.

Air Pollutants, Radioactive↗
PubMed1989

Computer modelling approach to study the modes of binding of alpha- and beta-anomers of D-galactose, D-fucose and D-glucose to L-arabinose-binding protein.

The modes of binding of alpha- and beta-anomers of D-galactose, D-fucose and D-glucose to L-arabinose-binding protein (ABP) have been studied by energy minimization using the low resolution (2.4 A) X-ray data of the protein. These studies suggest that these sugars preferentially bind in the alpha-form to ABP, unlike L-arabinose where both alpha- and beta-anomers bind almost equally. The best modes of binding of alpha- and beta-anomers of D-galactose and D-fucose differ slightly in the nature of the possible hydrogen bonds with the protein. The residues Arg 151 and Asn 232 of ABP from bidentate hydrogen bonds with both L-arabinose and D-galactose, but not with D-fucose or D-glucose. However in the case of L-arabinose, Arg 151 forms hydrogen bonds with the hydroxyl group at the C-4 atom and the ring oxygen, whereas in case of D-galactose it forms bonds with the hydroxyl groups at the C-4 and C-6 atoms of the pyranose ring. The calculated conformational energies also predict that D-galactose is a better inhibitor than D-fucose and D-glucose, in agreement with kinetic studies. The weak inhibitor D-glucose binds preferentially to one domain of ABP leading to the formation of a weaker complex. Thus these studies provide information about the most probable binding modes of these sugars and also provide a theoretical explanation for the observed differences in their binding affinities.

Arabinose↗
PubMed2002

Computer modeling of airbag-induced ocular injury in pilots wearing night vision goggles.

BACKGROUND: Airbags have saved lives in automobile crashes for many years and are now planned for use in helicopters. The purpose of this study was to investigate the potential for ocular injuries to helicopter pilots wearing night vision goggles when the airbag is deployed. METHODS: A nonlinear finite element model of the human eye was created. Ocular structures such as the fatty tissue, extraocular muscles, and bony orbit were included. The model was imported into Madymo (Mathematical Dynamical Models) and used to determine the worst-case position of a helicopter pilot wearing night vision goggles. This was evaluated as the greatest Von Mises stress in the eye when the airbag was deployed. RESULTS: The worst-case position was achieved by minimizing the distance between the eyes and goggles, having the occupant look directly into the airbag, and making initial contact with the airbag halfway through its full deployment. Simulations with the goggles both remaining fastened to and breaking away from the aviator helmet were performed. Finally, placing a protective lens in front of the eyes was found to reduce the stress to the eye but increase the force experienced by the surrounding orbital bones. CONCLUSION: The finite element model of the eye proved effective for evaluating the experimental parameters.

Accidents, Aviation↗
PubMed1976

DNA-histones, a computer model.

The model of DNA-histones has the following elements: 1. The hydrogen bonds between the complementary nucleotide bases function as informational gates. When the electrons pi of one nucleotide base are excited, an exchange of protons is produced between the two complementary bases. The result is the displacement of the conjugated double bonds which facilitates the inter-molecular transmission of the electronic wave of excitation by electro-magnetic coupling. 2. Each triplet of nucleotide bases of DNA fixes one definite amino acid (as in the genetic code). Between the nucleotide bases and the amino acids there are constituted informational gates, which ensure the circulation of the electronic wave of excitation. 3. An input signal molecule arrives at the receiver gene and unleashes the activity of the enzymes which introduce in the DNA-histones system the electronic wave of excitation. The electronic wave of excitation arises as a result of the break of the high-energy bonds of ATP. Then, the electronic excitation is transmitted to the productor gene where it represents the signal for starting the synthesis of the mRNA.

Adenosine Triphosphate↗
PubMed2001

Artificial cytochrome b: computer modeling and evaluation of redox potentials.

We generated atomic coordinates of an artificial protein that was recently synthesized to model the central part of the native cytochrome b (Cb) subunit consisting of a four-helix bundle with two hemes. Since no X-ray structure is available, the structural elements of the artificial Cb were assembled from scratch using all known chemical and structural information available and avoiding strain as much as possible. Molecular dynamics (MD) simulations applied to this model protein exhibited root-mean-square deviations as small as those obtained from MD simulations starting with the crystal structure of the native Cb subunit. This demonstrates that the modeled structure of the artificial Cb is relatively rigid and strain-free. The model structure of the artificial Cb was used to determine the redox potentials of the two hemes by calculating the electrostatic energies from the solution of the linearized Poisson-Boltzmann equation (LPBE). The calculated redox potentials agree within 20 meV with the experimentally measured values. The dependence of the redox potentials of the hemes on the protein environment was analyzed. Accordingly, the total shift in the redox potentials is mainly due to the low dielectric medium of the protein, the protein backbone charges, and the salt bridges formed between the arginines and the propionic acid groups of the hemes. The difference in the shift of the redox potentials is due to the interactions with the hydrophilic side chains and the salt bridges formed with the propionic acids of the hemes. For comparison and to test the computational procedure, the redox potentials of the two hemes in the native Cb from the cytochrome bc(1) (Cbc(1)) complex were also calculated. Also in this case the computed redox potentials agree well with experiments.

Amino Acid Sequence↗
PubMedDate not supplied

Computer models of albumin and haemoglobin glycation.

UNLABELLED: Two first-order mathematical models were developed to mimic the glycation of haemoglobin (H) and albumin (A). The total concentrations of A and H were assumed to be constant. The responses of the two models to varying blood glucose level were compared. The parameters of the haemoglobin model were not numerically estimated, only an informal fit was performed using clinical and published data. Nonlinear regression analysis was used to estimate the parameters of the albumin model. The level of glycated A (GA) was derived from the measured fructosamine level. Three diabetics were monitored daily for the level of fructosamine and blood glucose profile over a period of 10, 16 and 21 days, respectively. CONCLUSIONS: (1) The difference between GA and glycated H (GH) resulting from different elimination rates is decreased by the stratification of erythrocyte population. (2) Both GA and GH seem to have higher elimination rates than their nonglycated equivalents.

Blood Glucose↗
PubMed2003

Towards a computational model for -1 eukaryotic frameshifting sites.

MOTIVATION: Unconventional decoding events are now well acknowledged, but not yet well formalized. In this study, we present a bioinformatics analysis of eukaryotic -1 frameshifting, in order to model this event. RESULTS: A consensus model has already been established for -1 frameshifting sites. Our purpose here is to provide new constraints which make the model more precise. We show how a machine learning approach can be used to refine the current model. We identify new properties that may be involved in frameshifting. Each of the properties found was experimentally validated. Initially, we identify features of the overall model that are to be simultaneously satisfied. We then focus on the following two components: the spacer and the slippery sequence. As a main result, we point out that the identity of the primary structure of the so-called spacer is of great importance. AVAILABILITY: Sequences of the oligonucleotides in the functional tests are available at http://www.igmors.u-psud.fr/rousset/bioinformatics/.

Algorithms↗
PubMedDate not supplied

Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling.

Ten adult patients with persistent active HHV-6 variant A infection and clinical chronic fatigue syndrome (CFS) were studied over a period of 24 months after initial clinical diagnosis. CFS was diagnosed according to IIIP-revised CDC-criteria as defined by the CFS Expert Advisory Group to the German Federal Ministry of Health in 1994. Changes in HHV-6 antibody titer, viral DNA load, peripheral blood T lymphocytes and subpopulations, as well as CD4/CD8 cell ratio and cell death (apoptosis) were monitored. Data were collected for comparison with respective changes in acute HHV-6 infection and as a basis for future computer simulation studies. The results showed variable but slightly elevated numbers of HHV-6 DNA copies in the blood of patients with CFS, while PBL (peripheral blood lymphocyte) apoptosis rates were clearly increased. CD4/CD8 cell ratios varied from below 1 up to values as seen in autoimmune disorders. Contrary to acute HHV-6 infection, T lymphocytes do not exhibit the usual response to HHV-6, that is elevation of mature and immature populations suggesting a certain degree of unresponsiveness. The data suggest that persistent low-dose stimulation by HHV-6 may favor imbalanced immune response rather than overt immune deficiency. This hypothesis requires confirmation through additional functional studies.

Adolescent↗
PubMed1990

Computer modeling of surface coil sensitivity.

A simple model is presented for the calculation of relative signal-to-noise (S/N) ratios of coils of different sizes and configurations when applied to in vivo MRS. Axial symmetry is assumed, which enables rather simple expressions to be used for the calculation of coil loading by the tissue. The model is calibrated to experiments through measurement of the loaded and unloaded coil Q's. Applications of the model demonstrate that for small, superficial regions of interest (ROI), small surface coils can provide a S/N much improved over that of a larger coil. However, for very deep ROIs, larger coils or coils producing uniform B1 provide improved S/N.

Computer Simulation↗
PubMed2000

Estimation of torque on mechanical heart valves due to magnetic resonance imaging including an estimation of the significance of the Lenz effect using a computational model.

Mitral and aortic valve replacement is a procedure which is common in cardiac surgery. Some of these replacement valves are mechanical and contain moving metal parts. Should the patient in whom such a valve has been implanted be involved in magnetic resonance imaging, there is a possible dangerous interaction between the moving metal parts and the static magnetic field due to the Lenz effect. Mathematical models of two relatively common forms of single-leaflet valves have been derived and the magnitude of the torque which opposes the motion of the valve leaflet has been calculated for a valve disc of solid metal. In addition, a differential model of a ring-strengthener valve type has been considered to determine the likely significance of the Lenz effect in the context of the human heart. For common magnetic field strengths at present, i.e. 1 to 2 T, the effect is not particularly significant. However, there is a marked increase in back pressure as static magnetic field strength increases. There are concerns that, since field strengths in the range 3 to 4 T are increasingly being used, the Lenz effect could become significant. At 5 to 10 T the malfunction of the mechanical heart valve could cause the heart to behave as though it is diseased. For unhealthy or old patients this could possibly prove fatal.

Aortic Valve↗
PubMed2006

Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6.

Formation of multiprotein complexes is a common theme to pattern a cell, thereby generating spatially and functionally distinct entities at specialised regions. Central components of these complexes are scaffold proteins, which contain several protein-protein interaction domains and provide a platform to recruit a variety of additional components. There is increasing evidence that protein complexes are dynamic structures and that their components can undergo various interactions depending on the cellular context. However, little is known so far about the factors regulating this behaviour. One evolutionarily conserved protein complex, which can be found both in Drosophila and mammalian epithelial cells, is composed of the transmembrane protein Crumbs/Crb3 and the scaffolding proteins Stardust/Pals1 and DPATJ/PATJ, respectively, and localises apically to the zonula adherens. Here we show by in vitro analysis that, similar as in vertebrates, the single PDZ domain of Drosophila DmPar-6 can bind to the four C-terminal amino acids (ERLI) of the transmembrane protein Crumbs. To further evaluate the binding capability of Crumbs to DmPar-6 and the MAGUK protein Stardust, analysis of the PDZ structural database and modelling of the interactions between the C-terminus of Crumbs and the PDZ domains of these two proteins were performed. The results suggest that both PDZ domains bind Crumbs with similar affinities. These data are supported by quantitative yeast two-hybrid interactions. In vivo analysis performed in cell cultures and in the Drosophila embryo show that the cytoplasmic domain of Crumbs can recruit DmPar-6 and DaPKC to the plasma membrane. The data presented here are discussed with respect to possible dynamic interactions between these proteins.

Animals↗
PubMed1994

Computer modeling analysis for enediyne chromophore-apoprotein complex of macromolecular antitumor antibiotic C-1027.

On the basis of the van der Waals and electrostatic potential energy calculations and energy minimization (EM), a model for the apoprotein-chromophore complex of C-1027 has been constructed by docking the apoprotein (Apo-C1027) and the chromophore (C1027-Chr). The model of the apoprotein-chromophore complex also suggests the most probable stereochemistry of the chromophore (8R,9S,13R,17R), specific interactions between Apo-C1027 and C1027-Chr, and the origin of the stabilization of the chromophore by the apoprotein. The acetylenic bond of C1027-Chr appears to be stabilized by (1) hydrophobic interactions with the bottom of the pocket of Apo-C1027, (2) orbital interaction with Cys36-Cys45 disulfide bond, (3) van der Waals contact with Pro76, and (4) pi-pi stacking with the benzene moiety of the chromophore. In this model, molecular dynamics (MD) simulation of the chromophore indicates that the acetylene bond distance (C2-C7) of the apoprotein-bound chromophore is longer than that of the unbound chromophore.

Amino Acid Sequence↗
PubMed1995

Computer modelling of the alpha-helical coiled coil: packing of side-chains in the inner core.

In order to predict the structure of alpha-helical coiled-coil proteins from their sequences, it is necessary to know how the side-chains pack in the interface between the alpha-helical strands. Since in alpha-fibrous proteins leucine is the most common residue at both the a and d positions of the heptad repeat, which form the inner core of the interface, we determined the lowest-energy conformation for a two-stranded coiled-coil with the sequence (LAALAAA)5. Coiled-coils were constructed using the Crick equations with a range of pitches, major helical radii and relative rotations of the two strands, and with different starting side-chain conformations. On energy minimisation, convergence occurred to a small number of structures. The lowest-energy coiled-coil had 2-fold rotational symmetry, an average pitch of 131 A and an average radius of 4.52 A; the leucine side-chain conformations were tt and g+t at the a and d positions. This coiled-coil was used as a former to determine the lowest-energy side-chain conformations for the 63 combinations of a and d residues that occur in the repeating heptad sequence of rat skeletal myosin. The leucine residues at the a and d positions of the central heptad were replaced by the a-d pair of interest and molecular dynamics simulations performed to allow the side-chains of these residues to explore conformational space. The lowest-energy side-chain conformation of a residue at an a or d position depends on the nature of the partnering residue, consistent with the fact that these side-chains pack against one another. In most cases the lowest-energy structure was symmetric but in a few cases the side-chains were asymmetrically disposed in the two strands. The local pitch is very sensitive to the nature of the residues in the inner core and varies over a twofold range. In contrast, the radius and relative rotation of the two strands were relatively insensitive to sequence.

Alanine↗
PubMed2005

3-D computational modeling of media flow through scaffolds in a perfusion bioreactor.

Media perfusion bioreactor systems have been developed to improve mass transport throughout three-dimensional (3-D) tissue-engineered constructs cultured in vitro. In addition to enhancing the exchange of nutrients and wastes, these systems simultaneously deliver flow-mediated shear stresses to cells seeded within the constructs. Local shear stresses are a function of media flow rate and dynamic viscosity, bioreactor configuration, and porous scaffold microarchitecture. We have used the Lattice-Boltzmann method to simulate the flow conditions within perfused cell-seeded cylindrical scaffolds. Microcomputed tomography imaging was used to define the scaffold microarchitecture for the simulations, which produce a 3-D fluid velocity field throughout the scaffold porosity. Shear stresses were estimated at various media flow rates by multiplying the symmetric part of the gradient of the velocity field by the dynamic viscosity of the cell culture media. The shear stress algorithm was validated by modeling flow between infinite parallel plates and comparing the calculated shear stress distribution to the analytical solution. Relating the simulation results to perfusion experiments, an average surface shear stress of 5x10(-5)Pa was found to correspond to increased cell proliferation, while higher shear stresses were associated with upregulation of bone marker genes. This modeling approach can be used to compare results obtained for different perfusion bioreactor systems or different scaffold microarchitectures and may allow specific shear stresses to be determined that optimize the amount, type, or distribution of in vitro tissue growth.

Algorithms↗
PubMed2006

Insights into cytoskeletal behavior from computational modeling of dynamic microtubules in a cell-like environment.

Microtubule dynamic instability plays a fundamental role in cell biology, enabling microtubules to find and interact with randomly distributed cargo and spatially localized signals. In vitro, microtubules transition between growth and shrinkage symmetrically, consistent with the theoretical understanding of the mechanism of dynamic instability. In vivo, however, microtubules commonly exhibit asymmetric dynamic instability, growing persistently in the cell interior and experiencing catastrophe near the cell edge. What is the origin of this behavior difference? One answer is that the cell edge causes the asymmetry by inducing catastrophe in persistently growing microtubules. However, the origin of the persistent growth itself is unclear. Using a simplified coarse-grained stochastic simulation of a system of dynamic microtubules, we provide evidence that persistent growth is a predictable property of a system of nucleated, dynamic, microtubules containing sufficient tubulin in a confined space--MAP activity is not required. Persistent growth occurs because cell-edge-induced catastrophe increases the concentration of free tubulin at steady-state. Our simulations indicate that other aspects of MT dynamics thought to require temporal or spatial changes in MAP activity are also predictable, perhaps unavoidable, outcomes of the "systems nature" of the cellular microtubule cytoskeleton. These include the mitotic increase in microtubule dynamics and the observation that defects in nucleation cause changes in the behavior of microtubule plus ends. These predictions are directly relevant to understanding of the microtubule cytoskeleton, but they are also attractive from an evolutionary standpoint because they provide evidence that apparently complex cellular behaviors can originate from simple interactions without a requirement for intricate regulatory machinery.

Cell Shape↗
PubMed2006

A connectionist computational model for epistemic and temporal reasoning.

The importance of the efforts to bridge the gap between the connectionist and symbolic paradigms of artificial intelligence has been widely recognized. The merging of theory (background knowledge) and data learning (learning from examples) into neural-symbolic systems has indicated that such a learning system is more effective than purely symbolic or purely connectionist systems. Until recently, however, neural-symbolic systems were not able to fully represent, reason, and learn expressive languages other than classical propositional and fragments of first-order logic. In this article, we show that nonclassical logics, in particular propositional temporal logic and combinations of temporal and epistemic (modal) reasoning, can be effectively computed by artificial neural networks. We present the language of a connectionist temporal logic of knowledge (CTLK). We then present a temporal algorithm that translates CTLK theories into ensembles of neural networks and prove that the translation is correct. Finally, we apply CTLK to the muddy children puzzle, which has been widely used as a test-bed for distributed knowledge representation. We provide a complete solution to the puzzle with the use of simple neural networks, capable of reasoning about knowledge evolution in time and of knowledge acquisition through learning.

Algorithms↗